title: Convergent effects of mouse Pet-1 deletion and human PET-1 variation on amygdala fear and threat processing.
abstract: Serotonin is critical for shaping the development of neural circuits regulating emotion. Pet-1 (FEV-1) is an ETS-domain transcription factor essential for differentiation and forebrain targeting of serotonin neurons. Constitutive Pet-1 knockout (KO) causes major loss of serotonin neurons and forebrain serotonin availability, and behavioral abnormalities. We phenotyped Pet-1 KO mice for fear conditioning and extinction, and on a battery of assays for anxiety- and depression-related behaviors. Morphology of Golgi-stained neurons in basolateral amygdala (BLA) and prelimbic cortex was examined. Using human imaging genetics, a common variant (rs860573) in the PET-1 (FEV) gene was tested for effects on threat-related amygdala reactivity and psychopathology in 88 Asian-ancestry subjects. Pet-1 KO mice exhibited increased acquisition and expression of fear, and elevated fear recovery following extinction, relative to wild-type (WT). BLA dendrites of Pet-1 KO mice were significantly longer than in WT. Human PET-1 variation associated with differences in amygdala threat processing and psychopathology. This novel evidence for the role of Pet-1 in fear processing and dendritic organization of amygdala neurons and in human amygdala threat processing extends a growing literature demonstrating the influence of genetic variation in the serotonin system on emotional regulation via effects on structure and function of underlying corticolimbic circuitry.
authors.affiliation: Department of Psychological and Brain Sciences, Center for the Integrative Study of Animal Behavior, Indiana University, Bloomington, IN, USA. Electronic address: wellmanc@indiana.edu.
authors.forename: Cara L
authors.initials: CL
authors.lastname: Wellman
authors.forename: Marguerite
authors.initials: M
authors.lastname: Camp
authors.forename: V Morgan
authors.initials: VM
authors.lastname: Jones
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: MacPherson
authors.forename: Jessica
authors.initials: J
authors.lastname: Ihne
authors.forename: Paul
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Mouna
authors.initials: M
authors.lastname: Maroun
authors.forename: Emily
authors.initials: E
authors.lastname: Drabant
authors.forename: Ryan
authors.initials: R
authors.lastname: Bogdan
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Hariri
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics; D003214:Conditioning, Classical; D004268:DNA-Binding Proteins / Q000235:genetics*; D003712:Dendrites / Q000648:ultrastructure; D004644:Emotions / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C474280:FEV protein, human; C484684:Fev protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors
keywords: 5-HTT; BLA; Basolateral amygdala; EtOH; FEV; Fear conditioning; KO; Medial prefrontal cortex; PL; PTSD; Pet-1, FEV; Pheochromocytoma 12 ets; Serotonin; Tph2; basolateral amygdala; ethanol; knockout; posttraumatic stress disorder; prelimbic cortex; the serotonin transporter; tryptophan hydroxylase-2; ventromedial prefrontal cortex; vmPFC